Condensed cyclopropyl amine derivatives



United States Patent 3,010,972 CONDENSED CYCLOPRO'PYL AMDNE DERIVATIVES Carl Kaiser, Haddon Heights, N .J., and Charles L. Zlrkle,

Advantageous compounds of this invention are represented by the following structural formula:

FORMULA II Berwyn, Pa., assignors to Smith, Kline & French Lab- 5 CH oratories, Philadelphia, Pa., a corporation of Pennsyl- R CHN Vania CH/ \RE No Drawing. Filed Mar. 18, 1960, Ser. No. 15,808

6 Claims. (Cl. 260-3305) 10 when: This invention relates to novel ring condensed cyclo- Y represents CH2 0 S of S02; proPyl amme derlvatlves Spemficany l'ammocycloprop' R represents hydrogen, chloro or trifluoromethyl inposi- [a]1ndenes, l-ammocyclopropafh]benzofurans and 1- tions 3 or 4; and aminocyclopropaflalthianaphthenes having valuable phar- R2 and R3 represent hydrogen methyl or, when taken macodynaml? actmty' together with N, piperidino.

More specifically the compounds of this lnvention alter or modify the central nervous system and are particularly partlclllarly advanfageolls and useful compound of useful in the animal organism as antidepressant, ataractic thls mvemlon 1S lammoL1a:6,6a'tetrahydmcycloprop' and hypotensive agents. Certain of these compounds f f possess the valuable characteristic, rapid onset of action. Thls mventlfm Flcludes nontoxlc Pharmaceuncauy The compounds of this invention further exhibit potent acceptable, acld addition salts of the above defined bases monoamine oxidase inhibitory properties which are assoforfned with Orgamc and morgamc aclds- Such Salts are ciated with antidepressant activity I easily prepared by methods known to the art. The 'base The new 1 aminocyc1opmp[ahndenes 1 amin0cyc10 1s reacted W1tl1 either the stolchrometric amount of or- [b]b .lf and 1 minocyclopmpa[b]thia game or inorganic acld in aqueous mlsclble solvent, such naphthsnes of this invention are represented by the as acetone or ethanol, with isolatlon of the salt by con lowing Structural formula; centration and cooling or an excess of the acld in aqueous immiscible solvent, such as ethyl ether or chloroform, FORMULA I with the desired salt separating directly. Exemplary of R: such organic salts are those with maleic, fumaric, ben- Rl I zoic, ascorbic, pamoic, succmic, bismethylene-salicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tar- 3 taric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic,palrnitic, itaconic, when. 01 v g yco 1c, p amlnobenzoic, glutamic, benzenesulfonic and Y l'apresents 2 0, S of 2 theophylline acetic acids as well as with the 8-halothe0- R represents hydrogen, chloro, bromo, fluoro, trlfiuorophyllines for example, S-chlorotheophylline and 8-brornomethyl methyl methoxy; and theophylline. Exemplary of such inorganic salts are 2 and 3 repfesem d ge lower pp when taken 0 those with hydrochloric, hydrobromic, sulfuric, sulfamic, togeiher Wlth Plpfindmo, N"PY1Thdmy1 or phosphoric and nitric acids. These salts may also be P prepared by the classical method of double decomposi- By the term lower y where used herein groups tion of appropriate salts which is well-known to the art. having from 1 to 4, preferably 1 to 2, carbon atoms The compounds of this invention are prepared accordare indicated. ing to thefollowing synthetic procedure:

M N2CHCO2C2H5 R I 1 1 M 1 t CHCO2C:H5 cn lOH' on -01; 1 R1 OH-OOCI (M R1 CH-OOOH cn on Y Y/ -OH A CH R I I err-0on3 R, I OHN=O=O /CH on Y I Y/ OH R2 4 R1 OHN R; I 1 J) CH -N H1- OH/ H/ R3 Y"1 v Y The terms Y, Y R and R are as previously defined.

The properly substituted indene, benzofuran or thianaphthene starting material is reacted with at least one molar equivalent of ethyl diazoacetate at elevated temperature, preferably at the reflux temperature of the mixture. The resulting ethyl 1-cycloprop[a]indenecarboxylate or the corresponding benzofuran or thianaphthene compound is hydrolyzed with an alkali metal hydroxide such as potassium or sodium hydroxide to give the carboxylic acid. Treatment of this carboxylic acid with a chlorinatingagent such as phosphorus trichloride, phosphorus pentachloride or, preferably, thionyl chloride yields the corresponding carbonyl chloride.

The carbonyl chloride in an inert, water soluble, organic solvent such as acetone, tetrahydrofuran or dioxane is cooled to about -15" C. and treated with an CHO ' amino-la,6a-dihydro-1H-cyclopropa[b]benzofuran hydrochloride or the l-amino-la,6a-dihydroall-l-cyclopropa-' [b]thianaphthene hydrochloride. The free base is obtained by dissolving the hydrochloride salt in water,

neutralizing with an alkali metal hydroxide or carbonate such as sodium hydroxide or potassium carbonate and extracting with a water-immiscible, organic solvent such as ether or chloroform. Evaporation of the solvent from prop[a]indenes, l amino 1a,6a dihydro- 1H- cyclopropa[b]benzofurans and l-amino-1a,6a-dihydro- 1H-cyclopropa[b]thianaphthenes of this invention.

Al kylation" of the amino group to prepare further compounds of this invention is accomplished in several ways. Monoalkylation is carried out by reacting the primary amino compound with an appropriate aldehyde 7 orketone in a lower alcoholisolven't and 'catalytically reducing the resulting schifiubase with a catalyst such as palladium-on-charcoal or platinum oxide.

mary amino compound with at least two moles of an alkyl halide, such as a chloride or bromide, in the Monomethylation is. .lconveniently accomplished by 4 refluxing the primary amine with ethyl formate, and refluxing the resulting N-formyl compound with methyl iodide and a basic adjuvant such as an alkali metal hydride for example sodium hydride. The dimcthylamino derivatives are obtained by treating the primary amine with a mixture of aqueous formaldehyde and formic acid.

To obtain the piper-idino, N-pyrrolidinyl or morpholino compounds of this invention, the primary amine is heated with at least a molar equivalent of a polymethylene dihalide or a bisQS-dihaloethyhether and an acid binding agent such as pyridine or an alkali metal carbonate such as potassium or sodium carbonate.

The substituted indene, benzofuran and thianaphthene starting materials (111) are either known to the art or are prepared by the following procedures:

CH=OHC 01H CHaCHzC O OH GHzCHzCOCl occrn KU g (III) with aluminum chloride; the resulting ketoindane' is hy- Y the extracts gives the l-amino-l,la,6,6a tetrahydrocyclo-. V

The div ,alkylamino compounds are prepared by reacting the priv presence of a base such as an alkali metal; hydride or" carbonate for example "sodium hydride orfpotassium car- .bonate. 7

drogenated to give the hydroxyindane compound; the hydroxyindane is reacted with acetic anhydride and the resulting'ester is converted by pyrolysis to the indene starting materiah The benzofur an starting materials are prepared by reacting an appropriately substituted salicylaldehyde with chloroacetic acid in the presence of an alkali metal hydroxide such as sodium or potassium hydroxide at about 200 C.

The thianaphthene starting materials are prepared by the following procedure:'

a x 00 on B1 1 OH 7 R1 1 a a s srt CICH2CO2C2H5 V 8 A 0001 coon 11 w I Rt l CH2 7 CH2 s/ s V chloro'acetatein t-he presence of a basic adiuvant such as an alkali metal hydroxide for'example, sodium or potas- T'h e'; substituted thiophenol is condensed with ethyl.

sium hydroxide; the resulting ethyl ester is hydrolyzed; the acid is chlorinated; the resulting acid chloride is cyclized under Friedel-Crafts conditions with aluminum chloride and dehydrated with zinc-acetic acid to give the thianaphthene starting materials.

The compounds of this invention may be present as cis or trans isomers and also as d or 1 optical isomers. It is intended to include in this invention all of these isomers, the separated cis and trans isomers and the resolved 0. and l isomers as well as the mixtures of cistrans and d l isomers.

The following examples are not limiting but are illustrative of compounds of this invention and will serve to-make fully apparent all of the compounds embraced by the general formula given above.

Example 1 A cold mixture of 118.2 g. of indene and 121 g. of ethyl diazoacetate is stirred and slowly heated to reflux. The refluxing is continued for four hours. Distillation in vacuo gives ethyl 1,1a,6;6a-tetrahydro-1-cyc1oprop[a] indenecarboxylate.

A mixture of 56.5 g. of this ester in 300 ml. of ethanol and 33.6 g. of sodium hydroxide in 50 ml. of water is refluxed for nine hours. The solvents are evaporated in vacuo and the residue is dissolved in 500 ml. of water and acidified with concentrated hydrochloric acid. Extraction with ether and evaporation of the extracts yields 1,1 a,6,6a-tetrahydro-1-cycloprop[a] indenecarboxylic acid. The acid chloride is obtained by mixing 41 g. of the acid and 111 ml. of thionyl chloride, allowing the mixture to stand for 16 hours at room temperature, concentrating and distilling (B.P. 120131 C./1.5-3.1 mm.).

The acid chloride (23.5 g.) in 300 ml. of acetone is cooled to C. While stirring, a solution of 15.9 g. of sodium azide in 48 ml. of water is added, keeping the temperature below 13 C. The mixture is stirred for 30 minutes, poured into 1 l. of ice water and extracted with ether. The extracts are concentrated, then treated with 100 m1. of dry toluene and heated at 9095 C. for one hour. Removal of the solvent gives, as the residue, the isocyanate.

A mixture of 20.7 g. of this isocyanate and 350 ml. of concentrated hydrochloric acid is refluxed for five hours, then concentrated in vacuo. The residue is dissolved in water, and made basic. Extraction with ether and concentration of the extracts gives 1-amino-1,1a,6,6atetrahydrocycloprop [a] indene.

An ethanol solution of l-amino-l,1a,6,6a-tetral1ydrocycloprop[a]indene is treated with excess ethereal hydrogen chloride to separate the hydrochloride salt which is recrystallized from ethanol-ether to give crystals melting at 183184 C.

Example 2 A solution of 14.5 g. of 1-amino-1,1a,6,6a-tetrahydrocycloprop[a]indene, prepared as in Example 1, and 100 ml. of ethyl formate is refluxed for 17 hours, then concentrated in vacuo to leave, as the residue, l-formylamino-1,1a,6,6a-tetrahydrocycloprop[a]indene.

To a stirred solution of 17.3 g. of l-formylamino- 1,1a,6,6a-tetrahydrocyc1oprop[aJindene in 150 ml. of diethylene glycol dimethyl ether is added 5.2 g. of a 54.5% suspension of sodium hydride in mineral oil. The mixture is refluxed for two hours, then cooled and treated with an additional 5.2 g. of sodium hydride suspension.

Refluxing is continued for two hours, then 87 ml. of methyl iodide is added. The mixture is allowed to stand at room temperature for 16 hours, then refluxed for 12 hours. The mixture is filtered and concentrated and the residue is poured into one liter of ice water. Extraction with methylene chloride and evaporation of the extracts gives l,1a,6,6a-tetrahydro-l(N-methyl-N-formyl) aminocycloprop [a] indene.

Refluxing the above prepared N-formyl compound with 150 ml. of 37% hydrochloric acid, washing with ether, concentrating, dissolving the residue in water, basifying The maleate salt is prepared by treating an ethyl acetate 7 solution of the base with a molar equivalent amount of maleic acid in ethyl acetate.

Example 3 A mixture of 6.0 g. of l-amino-l,1a,6,6a-tetrahydrocycloprop[a]indene (prepared as in Example 1), 10 ml. of 40% aqueous formaldehyde and 15 ml. of formic acid is refluxed for 18 hours. The cooled reaction mixture is treated with 5.5 ml. of concentrated hydrochloric acid and the solution is evaporated in vacuo. The residue is made alkaline with potassium hydroxide and extracted with ether. The extracts are evaporated to give 1,1a,6,6a, tetrahydro 1 dimethylaminocycloprop[a]indene.

An ethanol solution of the free base is treated with an excess of ethereal hydrogen chloride to yield the hydrochloride salt.

Example 4 A mixture of 30.0 g. of 5-chloroindene and 24.0 g. of ethyl diazoacetate is refluxed for four hours, then distilled to give ethyl 3-chloro-l,la,-6,6a-tetrahydro-l-cycloprop[a]indenecarboxylate.

Hydrolyzing this ester by refluxing with sodium hydroxide in aqueous ethanol for eight hours and working up as in Example 1 gives 3-chloro-1,la, 6,6a-tetrahydrol-cycloprop[a]indenecarboxylic acid which is treated with excess thionyl chloride at room temperature to give, after concentrating and distilling, the acid chloride.

Twenty-seven grams of the acid chloride in 250 ml. of acetone is treated with 16.0 g, of sodium azide in aqueous solution, keeping the temperature at 5l0 C.

Pouring the mixture into ice water, extracting with ether,

Refluxing a mixture of 13.0 g. of 6-methylindene and 12.0 g. of ethyl diazoacetate for four hours and distilling in vacuo furnishes ethyl 1,la,6,6a-tetrahydro-4-methyl-1- cycloprop[aJindenecarboxylate which is hydrolyzed by refluxing with sodium hydroxide in aqueous ethanol to give 1,1a,6,6a-tetrahydro-4-methyl-l-cycloprop[a]indenecarboxylic acid.

Treatment of this carboxylic acid with excess thionyl chloride furnishes the acid chloride which is reacted with sodium azide and then heated in toluene to yield the isocyanate.

A mixture of 6.8 g. of the isocyanate and ml, of concentrated hydrochloric acid is refluxed for five hours. The mixture is concentrated in vacuo. The residue is dissolved in water and made basic with sodium hydroxide. Extraction with ether and removal of the ether from the extracts leaves 1-amino-1,1a,6,6a-tetrahydro-4-methylcycloprop[a]indene. I

A solution of 1.0 g. of the free basein 50 ml. of ether is treated with excess tartaric acid. Filtration gives the tartrate salt.

Example 6 7 ten hours. Working up as in Example 1 gives l,1a,6,6atetrahydro- 3 -methoxy 1 cycloprop[alindenecarboxylic acid which is treated with 50 ml. of thionyl chloride, and the resulting mixture distilled to give 1,1a,6,6a-tetrahydro-3-methoxy-1-cycloprop[a]indenecarbonyl chloride.

Treating this acid chloride with 18.0 g. of sodium azide at 10 C. and heating the resulting carbonyl azide with dry toluene at 90 C. for one hour gives the corresponding isocyanate. i

This isocyanate (15.0 g.) is heated at reflux with 250 ml. of concentrated hydrochloric acid for five hours. Working up as in Example 5 gives 1-amino-1,1a,6,6atetrahydro-3-rnethoxycycloprop [a] indene.

The free base (1.0 g.) in ethanol solution is treated with an excess of ethereal hydrogen bromide to separate the hydrobromide salt.

Example 7,

A mixture of 1.7 g. of 1amino-1,1a,6,6a-tetrahydro-3- methoxy-cycloprop[aJindene (prepared'as in Example 6), 3.0 g. of n-butyl bromide, 5.0 g. of potassium carbonate and 60 ml. of toluene is heated at reflux for ten hours.

The cooled reaction mixture is poured into Water and the Treatment of 17.6 g. of 1-a,6a dihydro 1H cyclopropa[b] benzofuran-l-carboxylic' acid with 50 ml. of thionyl chloride at room temperature for 16 hours and distillation gives the acid chloride which is reacted with sodium azide (15.0 g.) in acetone-water at 10 C. Heating the resulting carbonyl azide in toluene gives the corresponding isocyanate.

This isocyanate (8.5 g.) is refluxed with 150 ml. of concentrated hydrochloric acid. The mixture is concentrated in vacuo and the residue is dissolved in Water, made basic 7 and extracted with ether. Evaporation of the solvent from the extract gives 1 amino 1a,6a dihydro 1H cyclo- V propa[b]benzofuran.

Dissolving the free base in ethanol and treating with an excess of ethereal hydrogen chloride gives the hydrochloride salt. 7 I

Y sExample 9 -A mixture of 14.7 g: of l-arnino-lafia dihydro-lH- cyclopropa[b]benzofuran (prepared as in Example 8), 22.9 g. of 1,5-dibromopentane and 30.0 g. of potassium carbonate in 200 ml. of xylene is refluxed for 14 hours. The cooled reaction mixture. is treated with water. The xylene layer is separated and evaporated in vacuo to leave, as the residue, 1-a,6a dihydro l piperidino -jlH cyclopropa[b]benzofuran.

A solution of the free base (1.0 g.) in ml. of ether is reacted with an excess of glacial acetic acid to yield the acetate salt.

i ExZzmple 10 S-chlorobenzoturan (15.2 g.) and 12.0 g. of ethyl diazoacetate are refluxed for four hours.' Distillation gives ethyl 3-chloro 1a,6a dihydro-lH-cyclopropa [a]ben1ofuran-l-carboxylate. 1 z

Hydrolysis of this ester by refluxing With-.SOdlllIIlhypropa[b]benzofuran-l-carbonyl chloride.

A 'cold solution of 11.8 g. of the above prepared acid chloride in 125 ml. of acetone istreated'with an aqueous solution of 8.0 g. of sodium azide keeping the temperature below 13 C The mixtureis stirred for.30 minutes, then poured into 1 liter of ice water and extracted with ether.

? droxide and chlorination of the resulting acid with thionyl chloride gives 3 chloro 1a,6a dihydro 1H cyclo- Example 11 A mixture of 14.8 g. of 7-methoxybenzofuran and 12.0 g. of ethyl diazoacetate is refluxed for four hours and then distilled to give ethyl la,6a dihydro 5 methoxy 1H cyclopropa [b] benzoturan-l-carboxylate. V

' Ten grams of this ester in 60 ml. of ethanol and 8 g. of sodium hydroxide in 15 ml. of Water are heated at reflux for nine hours. Working up as in Example 1 gives the carboxylic acid. Treating this acid with 30 ml. of thionyl chloride at room temperature for 16 hours and then distilling gives 1a,6-a dihydro 5 methoxy 1H cyclopropa[blbenzofuran-l-carbonyl chloride.

'An acetone solution of this acid chloride (5.0 g.) is treated with 4.0 g. of sodium azide in aqueous solution at 5 13 C. Working up as in Example 10 and heating the resulting carbonyl azi'de with toluene gives, after re vmoval of the toluene, the corresponding isocyanate.

Refluxing 2.1 g. ofthis isocyanate with 35 m1. of concentrated hydrochloric acid for five hours, evaporating, dissolving the residue in 'water, basifying, extracting with ether and evaporating the extract give-s 1-amino-1a,6a-dihydro-S-methoxy-lH-cyclopropa [b] benzofuran.

An ethyl acetate solution of the free base is treated with an equal molar amount of maleic acid to give, upon 'concentration and cooling, the maleate salt.

Example 12 A mixture of 38.4 g. or" 1a,6a-dihydro-lH-cyclopropa[b]thianaphthene-l-carboxylic acid and 100 m1. of thionyl chloride is allowed to stand for 16 hours and then distilledto give the carbonyl chloride. Treatment of this acid chloride in acetone solution with 30.0 g. of sodium azide in water at 10 C. gives the carbonyl azide. The isocyanate is prepared by heating this carbonyl azide in dry toluene at 9095 C. for one hour and removing the solvent in vacuo.

A mixture of 20.0 g. of the above prepared isocyanate and 300 ml. of concentrated hydrochloric acid is refluxed for live hours. Concentrating in vacuo, dissolving the residue in water, basifying with sodium hydroxide, extracting with ether and removing the ether from the extract gives l-amino-1a,6a-dihydro-lH-cyclopropa[blthianaphthene; The free base (1.0 g.) in ml. of ethanol is treated with an excess of ethereal hydrogen chloride to give the hydrochloride salt.

Example 13 V S-chlorothianaphthene (16.8 g.) and ethyl diazoacetate (12.0 g.) are heated at reflux for four hours,' then dis tilled to give ethyl 3-chloro-1a,6a-dihydro-lH-cyclopropa- [b] thianaphthenel-carb oxylate.

.,Refluxing this ester (15.0 g.) in 100 ml. of ethanol with 8.0 g. of sodium hydroxide in 20 ml. of Water for nine hours and Working up as in Example 1 gives 3- chlo'ro 1a,6a-clihydro-lH-cyclopropa[b]thianaphthene- 1-carboxylic acidl Treatment of this'ac'id with 50 ml. of thionyl chloride at. room temperature gives the corresponding acid chloride which is reacted with 12 g. of sodium azide The resulting carbonyl azide is heated in toluene at l00 C. for one hour to give the isocyanate] Refluxing thisjisocyanate with 200 ml. of concentrated hydrochloric acid and working up as in Example l2-yields 1- amino 3-chloro-la,6a-dihydro-lH-cyclopropa[b1thianaphthene. i

An ethanol solution of the free base is treated with excess ethereal hydrogen chloride to give'the hydrochloride salt." 5 a Example 14 A mixture of 21.3 g. of 4-bromothianaphthene and 12.0 g. of ethyl diazoacetate is refluxed for four hours. Distillation gives ethyl 2-bromo-1a,6a-dihydro-1H-cyclopropa[blthianaphthene-l-carboxylate.

Hydrolysis of this ester by refluxing with sodium hydroxide in aqueous ethanol and chlorinating the resulting carboxylic acid with thionyl chloride gives 2-bromo- 1a,6a dihydro 1H-cyclopropa[b]thionaphthene-l-carbonyl chloride.

A solution of 14.4 g. of this acid chloride in 150 ml. of acetone is cooled to 5 C. and treated with an aqueous solution of 8.0 g. of sodium azide. The resulting mixture is stirred for 30 minutes and worked up as in Example to give the carbonyl azide which is heated in dry toluene for one hour at 9095 C. to give the isocyanate.

Refluxing this isocyanate (13.4 g.) with 150 ml. of concentrated hydrochloric acid for five hours, then concentrating, dissolving the residue in water, basifying, extracting with ether and evaporating the extract gives 1- amino 2 bromo-la,6a-dihydro-1H cyclopropa[b]thianaphthene.

Example theme is obtained.

A solution of 2.0 g. of the base in ethyl acetate is treated withexcess citric acid. Concentration and cooling gives the citrate salt.

Example 16 6-methoxythianaphthene (16.4 g.) and ethyl diazoacetate (12.0 g.) are refluxed together for four hours and then distilled to give ethyl 1a,6a-dihydro-4-methoxy- 1H-cycl0propa[b]thianaphthene-l-carboxylate. .Refluxing this ester with 12.0 g. of sodium hydroxide in aqueous ethanol for nine hours gives the carboxylic acid which is treated with 40 ml. of thionyl chloride at room temperature for '16 hoursto give, upon distillation, 1a,6a-dihydro- 4 methoxy-lH-cyclopropa[b]thianaphthene-l-carbonyl chloride.

The above prepared acid chloride (12.0 g.) is stirred with 7.5 g. of sodium azide in acetone-water at 5-l3 C. for 30 minutes. The mixture is poured into ice water and extracted with ether. The extract is concentrated and then treated with dry toluene and heated at 9095 C. for one hour to give, after removal of the solvent, the corresponding isocyanate.

Refluxing the isocyanate with 100 ml. of concentrated hydrochloric acid and working up as in Example 14 gives 1 amino -1a,6a-dihydro-4-rnethyl-lH-cyclopropa[b]thianaphthene.

The hydrochloride salt of this base separates when an ethanol solution of the free base is treated with an excess of ethereal hydrogen chloride.

Example 17 A mixture of 3.9 g. :ot l-amino-1a,6a-dihydro-4-methoxy-lH-cyclopropa[blthianaphthene (prepared as in Example 16), 2.8 g. of biS-(B-CihllOrOSllhYDethCd, 5.5 g. of

potassium carbonate and 75 ml. of xylene is refluxed for Example 18 p-Trifluoromethylbenzaldehyde (17.4 g.) is heated with 10 a mixture of 55 ml. of acetic anhydride and 8.7 g. of sodium acetate at 170-175 C. for eight hours. The reaction mixture is poured into water and acidified with concentrated hydrochloric acid. The p-trifluoromethylcinnamic acid is filtered otf.

Fifteen grams of p-trifluoromethylcinnamic acid is hydrogenated in ml. of absolute ethanol solution with 0.15 g. of platinum oxide at 50 p.s.i. for 78 hours at room temperature. The mixture is filtered and concentrated in vacuo to give p-trifluoromethyldihydrocinnamic acid.

Treatment of 12.0 g. of the above prepared acid with 25 ml. of thionyl chloride at room temperature for 16 hours and concentration of the mixture in vacuo gives ptrifluoromethyldihydrocinnamoyl chloride.

This acid chloride in light petroleum is warmed with about 12 g. of anhydrous aluminum chloride until evolution of hydrogen chloride ceases. The mixture is cooled, treated with water and steam distilled. The distillate is saturated with sodium sulfate and the organic layer is separated, washed with sodium carbonate solution and with water and stripped in vacuo to give 6-trifluoromethyll-indanone.

This indanone (11 g.) is refluxed with 2 g. of lithium aluminum hydride in 500 ml. of absolute ethanol for 20 minutes. The mixture is diluted with 100 ml. of ether, followed by 50 ml. of water. The organic layer is separated and evaporated to give 6-trifluoromethyl-l-indanol.

A mixture of 9.5 g. of 6-trifluoromethyl-1-indanol and 50 ml. of acetic anhydride is refluxed for two hours. The excess acetic anhydride is removed in vacuo and the residue is diluted with water and extracted with ether. Removal of the solvent in vacuo gives 1-acetoxy-6-trifluoromethylindane.

The above prepared 1-acetoxy-6-trifluoromethylindane is slowly dropped through a column packed with glass helices while maintaining an internal temperature of 460 C. The vapors are collected in a cooled flask. Upon completion of the addition of the acetoxy compound the column is flushed with 5 ml. of anhydrous benzene The product collected in the flask is diluted with 200 ml. of water and extracted with ether. The extract is washed with sodium carbonate, dried, evaporated and distilled to give 5 -trifluoromethylindene.

A mixture of 9.2 g. of S-trifluoromethylindene and 6.0 g. of ethyl diazoacetate is refluxed for four hours. Distillation furnishes ethyl 1,1a,6,6a-tetrahydro-3-trifluoromethyl-l -cycloprop [a] indenecarboxylate.

Hydrolysis of this ester by refluxing with sodium hydroxide and chlorination by treating with thionyl chloride gives 1,la,6,6a-tetrahydro-3-trifluoromethyl-l-cycloprop- [a]-indenecarbonyl chloride. This acid chloride is treated with sodium azide and the resulting carbonyl azide is heatedin toluene to give the corresponding isocyanate.

A mixture of 8.0 g. of the isocyanate is refluxed with 100 ml. of concentrated hydrochloric acid for five hours, then concentrated in vacuo. The residue is dissolved in water, basified and extracted with ether. Evaporation of the extracts gives l-amino-l,la,6,6a-tetrahydro-3-trifluoromethylcycloprop[a]indene. i v

The hydrochloride salt is prepared by treating an ethanol solution of the free base with excess ethereal hydrogen chloride.

Example 19 p-Trifluoromethylaniline (120.0 g.) is added slowly to a mixture of ml. of concentrated hydrochloric acid capto) acetate.

solution is refluxed with 160g. of potassium hydroxide for eight hours. 7 The alcohol is removed by distillation,-

Water is added to the residue and the aqueous mixture is washed with ether. The aqueous mixture is made strongly acidwitn concentrated sulfuric acid and is then steam distilled. The lower layer is separated and redistilled't o obtain p-triiluoromethylthiophenol.

To a mixture of 17.8 g. of p-trifluoromethylthiophenol and 4.0 g. of sodium hydroxide in aqueous solution is added 12.2 g. of ethyl chloroacetate over 30 minutes keeping the temperature at 25 C. The reaction mix-.

ture is extracted with ether and the extract evaporated and distilled to give ethyl (4-trifluoromethylphenylmer- This ester ishydrolyzed by refluxing in sodium hydroxide solution for live hours, evaporating, dissolving the residue in water, acidifying, extracting with ether and evaporating the solvent in vacuo to give 4-trifluoromethylphenylmercaptoacetic acid. The acid chloride is obtained by treating 15.0 g. of the acid with 50 ml.

of thionyl chloride at room temperature for 16 hours.

zinc dust is refluxed with. stirring for three hours. The cooled mixture is made alkaline with sodium hydroxide and steam distilled. The distillate is extracted with ether.v Concentration of the extract and distillation of the residue gives 5-trifluoromethylthianaphthene.

Refluxing 10.1 v of 5-trifluoromethylthianaphthene with 6.0 g. of ethyl diazoacetate for four hours and then distilling gives ethyl 1a,6a-dihydro-3-trifiuoromethyl1I-lcyclopropa[b]thianaphthene-l-carboxylate. This ester is hydrolyzed by refluxing with sodium hydroxide in aqueous ethanol. The resulting carboxylic acid is treated with thionyl chloride to give 1a,6a-dfihydro-3-trifluoromethyl-lH-cyclopropalb]thianaphthene-l-carbonyl chloride. Reacting this acid chloride with sodium azide and heating the resulting carbonyl azide in toluene at 95 C. for one hour gives the isocyanate.

This isocyanate (6.0 g.) and 75 ml. of concentrated hydrochloric acid are heated at reflux forfive hours;

Working up as in Example 18 gives 1-amino-la,6a-dihydro-i3 -trifluoromethyl-1H-cyclopropa[b] thianaphthene.

A solution of 1.0 g; of the free base in ethyl acetate is added to an ethanol solution of mandelic acid. Concentration and cooling yields the mandelate salt. I,

Example 20.

v A mixture of 4.6 g. of l-amino-la,6a-dihydro-3- trifluoromethyl-lH-cyclopropa[b]thianaphthene, prepared as in Example 19, and 40 ml. of acetaldehyde in ethanol is stirred at room temperature 'for live hours. The solution is concentrated in vacuo and the residue is hydrogenated with 0.2. g. of 'palladiummn-charcoal in ethanol solution at 50 p.s.i. for two hours. Filtration and evaporation of the solvent gives, as the residue, tl-ethylamino- 1a,6a dihydro-3-trifluoromethyl-IH-cyclopropa[blthia- 'naph-thene Example 21 fluoromethyl-1H-cyclopropa[b]thianaphthene, 2.2. g, of

' ethyl bromide, 2.5 g; of sodium carbonate and 50 ml. of

toluene is refluxed for six hours. The cooled .rnixture is poured into water. The organiclayer is concentrated" of. 10.9 g. of 5trifluoromethyl-3(2H) thianaphthenone, 60 ml. of glacial acetic acid and 15 ml. of V I in which Y a..rnember selected from the group min I 3 r i A mixture of 2.3 g. of l-amiuo-laa-dihydro-tn- 12 in vacuo to give l-diethylamino-ia,6a-dihydro-3-trifluoromethyl-lH-cyclopropafib]thianaphthene. The free base is dissolved in ethanol and treated with excess ethereal hydrogen chloride to give l-diethylamino-1a,6a-dihydro- S-trifluoromethyl-lH-cyclopropa[b]thianaphthene hydrochloride.

Example 22 A mixture of 14.0 g. of S-fluoroslicylaldehyde, 9.4 g.

of chloroacetic acid and 11.2 g. of potassium hydroxide in aqueous ethanol is heated at 160-180 C. for 12 hours. The mixture is 'then steam distilled. The distillate is extracted with ether and the extract is concentrated and distilled to give S-fluorobenzofuran.

Refluxing 13.6 g. of S-iluorobenzofuran with 12.0 g. of ethyl diazoacetate for four hours and then distilling gives ethyl S-fluoro-la,6a-dihydroJH-cyclopropa[b]benzofuran-il-carboxylate.

This ester is hydrolyzed by refluxing with 12g. of sodium hydroxide in aqueous ethanol for nine hours and the resulting carboxylic acid is treated with thionyl chloride at room temperature to give, after concentrating and distilling, 3-fluoro-1a,6a-dihydro-1H-cyclopropa[b]-benzofuran-l-carbonyl chloride.

An acetone solution of the above prepared acid chloride (10.6 g.) is cooled to 5 C. and treated with 14.0 g. of sodium azide in aqueous solution. The mixture is stirred for 30 minutes at 5-l3 C., then poured into ice water and extracted with ether. The extract is concentrated, treated with dry toluene and heated at 95 C.

for one hour to give, after removal of the solvent, the

corresponding isocyanate.

Refluxing 10.0 g. of this isocyanate with .150 ml. of

concentrated hydrochloric acidand working up as in Example 1 gives 1-amino-3-fiuoro-la,6a-dihydro-lH-cyclo. pro-pa{b]benzofuran.

The free'b'ase in ethanol solution is treated with an excess of ethereal hydrogen chloride to give the hydrochloride salt.

Example 23 in Example 22 gives the carbonyl azide which is heated 111 toluene'at C. for one hour to furnish the isocyanate. a V

Heating this isocyanate (4.3 g.) with 60 ml. of hydrochloric acid at reflux for five hours and working up as in Example l gives 1-amin0-1a,6a-dihydro-6,6-dioxo-1H- cyclopropa [b thianaphthene.

What is claimed is: l. A chemical compound of the class consisting of a 'free base and its nontoxic; pharmaceutically acceptable,

acid addition salts, the free base having the following formula: I I

' fiuoro, trifluorornethyl, methyl and methoxy; andR and R are members selected from thegroup consisting of piperidino, N-pyrrolindinyl and morpholino.

hydrogen, lower alkyl and, when taken together with N,

13 14- 2. l-amino-l,1@696a-tetrahydrocycloprop[a]indene. 6. 1-am1'no-1a,6a-dihydro-1H-cyclopropa[a] thianaph- 3. 1 amino-1,1a,6,6a-tetrahydrocycloprop[a]-indene thene. hydrochloride.

4. l-amino 3 chloro-l,1a,6,6atetrahydrocycloprop- References Cited in the file of this Patent [a]indene.

5 Badger: Journal of the Chemical Society, (London), 5. 1 amino-1a,6a-d1-hydro-1H-cyclopropa[b]-benzo- 953 pages 1179 34 furan. 

1. A CHEMICAL COMPOUND OF THE CLASS CONSISTING OF A FREE BASE AND ITS NONTOXIC, PHARMACEUTICALLY ACCEPTABLE, ACID ADDITION SALTS, THE FREE BASE HAVING THE FOLLOWING FORMULA: 